Certain 2,4-diamino-5-(2,3-dihalophenyl)-6-substituted pyrimidines which are pharmacologically active CNS compounds

Abstract

A class of substituted phenylpyrimidine compounds are disclosed which are potent inhibitors of the excitatory amino acid, glutamate. Such compounds are useful in the treatment or prevention of a range of CNS disorders including cerebral ischaemic damage and epilepsy.

We claim: 
     
       1. A pyrimidine of formula (I): ##STR7## wherein: R 1  is selected from the group consisting of NH 2 , N--(C 1  -C 6  alkyl)amino and N,N-di(C 1  -C 6  alkyl)amino; R 2  is NH 2  ;   R 3  is trifluoromethyl or --CH 2  X wherein X is selected from the group consisting hydroxy, C 1  -C 6  alkoxy, phenoxy, benzyloxy and halo;   R 4  and R 5  are each halo; and   R 6  to R 8  are each hydrogen; and pharmaceutically acceptable acid addition salts thereof.     
     
     
       2. A compound according to claim 1 wherein R 1  is NH 2 . 
     
     
       3. A compound according to claim 1 wherein R 3  is fluoromethyl. 
     
     
       4. A compound according to claim 1 wherein R 3  is selected from the group consisting of methoxymethyl, trifluoromethyl, benzyloxymethyl and phenoxymethyl. 
     
     
       5. A compound according to claim 1, wherein R 4  and R 5  are each chloro. 
     
     
       6. A compound according to claim 1 wherein: R 1  is selected from the group consisting of NH 2 , N-ethylamino and N,N-dimethylamino;   R 2  is NH 2  ;   R 3  is selected from the group consisting trifluoromethyl, benzyloxymethyl and methoxymethyl;   R 4  and R 5  are each chloro; and   R 6  to R 8  are each hydrogen.   
     
     
       7. A compound according to claim 1 which is selected from the group consisting of: 2,4-diamino-5-(2,3,-dichlorophenyl)-6-trifluoromethylpyrimidine;   2,4-diamino-5-(2,3,-dichlorophenyl)-6-methoxymethylpyrimidine; and pharmaceutically acceptable acid addition salts thereof.     
     
     
       8. A compound according to claim 1 which is selected from the group consisting of: 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine;   2,4-diamino-5-(2,3-dichlorophenyl)-6-phenoxymethylpyrimidine; and   2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine.   
     
     
       9. A pharmaceutical formulation comprising a pharmaceutically effective amount of a pyrimidine of formula (I): ##STR8## wherein: R 1  is selected from the group consisting of NH 2 , N--(C 1  -C 6  alkyl)amino and N,N-di(C 1  -C 6  alkyl)amino; R 2  is NH 2  ;   R 3  is trifluoromethyl or --CH 2  X wherein X is selected from the group consisting of hydroxy, C 1  -C 6  alkoxy, phenoxy and benzyloxy and halo;   R 4  and R 5  are each halo; and   R 6  to R 8  are each hydrogen; or a pharmaceutically acceptable acid addition salt thereof; and one or more acceptable carriers therefor.     
     
     
       10. A formulation according to claim 9 wherein R 1  is NH 2 . 
     
     
       11. A formulation according to claim 9 wherein R 3  is fluoromethyl. 
     
     
       12. A formulation according to claim 9 wherein R 3  is selected from the group consisting of methoxymethyl, trifluoromethyl, benzyloxymethyl and phenoxymethyl. 
     
     
       13. A formulation according to claim 9 wherein R 4  and R 5  are each chloro. 
     
     
       14. A formulation according to claim 9 wherein R 1  is selected from the group consisting of NH 2 , N-ethylamino and N,N-dimethylamino; R 2  is NH 2  ; R 3  is selected from the group consisting of trifluoromethyl, benzyloxymethyl and methoxymethyl; R 4  and R 5  are each chloro; and R 6  to R 8  are each hydrogen. 
     
     
       15. A formulation according to claim 9 wherein the pyrimidine of formula (I) or salt thereof is selected from the group consisting of: 2,4-diamino-5-(2,3,-dichlorophenyl)-6-trifluoromethylpyrimidine;   2,4-diamino-5-(2,3,-dichlorophenyl-6-methoxymethylpyrimidine; and pharmaceutically acceptable acid addition salts thereof.     
     
     
       16. A formulation according to claim 9 wherein the pyrimidine of formula (I) or salt thereof is selected from the group consisting of: 2,4-diamino-5-(2,3-dichlorophenyl)-6-fluoromethylpyrimidine;   2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine; pharmaceutically acceptable acid addition salts thereof.     
     
     
       17. A formulation according to claim 9 which is in the form of capsules or tablets suitable for oral administration, each capsule and tablet containing an effective amount of said pyrimidine of formula (I) or salt thereof. 
     
     
       18. A formulation according to claim 9 which is suitable for parenteral administration and is presented in unit-dose containers.